Up to 20% of all individuals in the US are treated for an autoimmune and/or chronic inflammatory disease. Autoimmune diseases like Rheumatoid Arthritis (RA) and Systemic Lupus Erythematosus (SLE) are responsible for significant suffering and represent an enormous financial burden to the health care system. Despite the release of new therapies, many individuals remain refractory to treatment. Thus, there is still a very large unmet need to develop new medicines that can be used to treat autoimmune patients. Although we know that B cells, B lineage antibody (Ab) secreting cells (ASCs) and inflammatory cytokines all play important roles in driving clinical disease, we still lack a fundamental understanding of how acute or chronic inflammatory signals initiate commitment of B cells into the ASC lineage and whether B cells contribute to pathology only through their production of Abs or whether inflammatory effector B cells also contribute to immunity or immunopathology. We identified a unique population of circulating T-bethi pre-ASCs (DN2 cells) that are expanded in a subset of SLE and RA patients. We showed that these cells, which have also been observed in other autoimmune and chronic inflammatory settings, are associated with increased systemic inflammatory cytokines, pathogenic autoAbs and disease severity. We identified the inflammatory cytokine IFNg as key inducer of the T-bethi pre-ASC subset. We further showed that IFNg signals significantly enhance development of both mouse and human ASCs and determined that two IFNg-induced transcription factors (TFs), T-bet and IRF1, play important but distinct roles in IFNg-induced ASC development. In this application we are testing our central hypothesis that IFNg induces two mutually exclusive or competing cell fate programs in B cells ? a cytokine-producing effector cell fate and an ASC differentiation fate ? and that integration of signals from TLRs and other cytokines, like IL-2, cooperate with T-bet to repress the inflammatory fate and promote IRF1-mediated differentiation into ASCs. The immediate objectives of this proposal are to (i) determine how IFNg signals synergize with TLR, IL-2 and IL-21 to promote human ASC development and (ii) determine whether the balance between IRF1 and T-bet regulates the development of protective or damaging immune B cell mediated humoral and inflammatory responses in the setting of viral infection and autoimmunity. Our long-term goal is to use what we learn about how B cell fate decisions are programmed to identify interventions that can be that can prevent the formation, maintenance or function of potentially pathogenic B cell subsets. This research is significant because we will for the first time define at a molecular level how IFNg contributes to human B cell fate decisions and how two of the TFs induced by IFNg, T-bet and IRF1, cooperate to facilitate ASC development in the settings of acute infectious and chronic autoimmune disease. We expect that these studies, which are designed to reveal how IFNg-induced TFs modulate B cell fate decisions, may someday lead to new strategies for treatment of diseases, like SLE and RA, that are caused or exacerbated by inflammatory cytokines and pathogenic Abs. !